High-risk human papillomaviruses (HPVs) are etiological agents of cervical cancer, the second most common cause of cancer death in women worldwide. In addition, high-risk HPVs are also associated with a number of other anogenital tract carcinomas, including, anal, vulvar and penile cancers as well as approximately 20% of oral cancers. Despite the recent introduction of a prophylactic vaccine that is to protect from infection with some high-risk HPV types, it will be several decades before this will affect cervical cancer incidence and death rates. Currently 10 women succumb to cervical cancer every day in the US, alone. HPV-associated carcinogenesis is driven by HPV E6/E7 oncoprotein expression;these proteins not only contribute to induction of premalignant lesions, but also mechanistically contribute to malignant progression, a relatively rare event that generally occurs several years to decades after the initial infection. Progression is frequently associated with HPV genome integration into a host cellular chromosome, a terminal event for the viral life cycle. As a consequence, E6 and E7 are the only viral proteins that are consistently expressed in cervical cancers. This project is focused on investigating biological activities of high-risk HPV oncoproteins and to determine whether they could be harnessed as a novel therapeutic modality for high-risk HPV-associated lesions and cancers. In aim 1, it is proposed to determine the mechanistic basis of HPV16 E7-induced trophic sentinel signaling in human keratinocytes, a cellular tumor suppressor pathway that thwarts the proliferation of cells that have suffered oncogenic alterations, which lead to aberrant cell proliferation. Aim 2 is to determine the mechanistic basis of HPV16 E7-induced autophagy in human keratinocytes and if/how this is connected to trophic sentinel signaling. Since autophagy is an evolutionary ancient and conserved response to metabolic stress we will determine how HPV16 E7 expression causes increased metabolic requirements. Aim 3 is to investigate the mechanism by which HPV16 E6 abrogates HPV16 E7 induced trophic sentinel signaling. In this aim we will test whether small molecule inhibitors of the pathways that E6 and E7 may be targeting and that are currently in the clinic may be harnessed as a novel therapeutic modality for HPV-associated lesions and cancers. Since the cellular pathways that are targeted by the E6 and E7 oncoproteins are frequently rendered dysfunctional by mutation in non-HPV associated human solid tumors, these studies may also be applicable for therapy of other human cancers.